The article associated with this dataset is located in ORE at: http://hdl.handle.net/10871/124652This is the dataset used for the Reding et al. (2021) article "The Antibiotic Dosage of Fastest Resistance Evolution: gene amplifications underpinning the inverted-U" published in Molecular Biology and Evolution.Engineering and Physical Sciences Research Council (EPSRC)Ramón Areces Postdoctoral FellowshipMinisterio de Ciencia, Innovación y Universidades/FEDE

Beardmore, R

Bergmiller, T

Catalán, P

Gudelj, I

Jansen, G

Reding, C

Rosenstiel, P

Schulenberg, H

Wood, E

Molecular Biology and Evolution

To determine the dosage at which antibiotic resistance evolution is most rapid, we treated Escherichia coli in vitro, deploying the antibiotic erythromycin at dosages ranging from zero to high. Adaptation was fastest just below erythromycin’s minimal inhibitory concentration (MIC) and genotype-phenotype correlations determined from whole genome sequencing revealed the molecular basis: simultaneous selection for copy number variation in three resistance mechanisms which exhibited an “inverted-U” pattern of dose-dependence, as did several insertion sequences and an integron. Many genes did not conform to this pattern, however, reflecting changes in selection as dose increased: putative media adaptation polymorphisms at zero antibiotic dosage gave way to drug target (ribosomal RNA operon) amplification at mid dosages whereas prophage-mediated drug efflux amplifications dominated at the highest dosages. All treatments exhibited E. coli increases in the copy number of efflux operons acrAB and emrE at rates that correlated with increases in population density. For strains where the inverted-U was no longer observed following the genetic manipulation of acrAB, it could be recovered by prolonging the antibiotic treatment at subMIC dosages.P.C. was supported by a Ramón Areces Postdoctoral Fellowship and by Ministerio de Ciencia, Innovación y Universidades/FEDER (Spain/UE) through Grant numbers PGC2018-098186-B-I00 (BASIC) and PID2019-109320GB-I00. RB and CR were supported by UKRI(EPSRC) grants EP/N033671/1 and EP/I00503X/1, EW was supported by a UKRI(BBSRC) DTP block grant (SWBio) awarded to Exeter University

Reding, Carlos

Catalan Fernandez, Pablo

Jansen, Gunther

Bergmiller, Tobias

Wood, Emily

Rosenstiel, Phillip

Schulenburg, Hinrich

Gudelj, Ivana

Beardmore, Robert

Universidad Carlos III de Madrid e-Archivo

English

The antibiotic dosage of fastest resistance evolution: Gene amplifications underpinning the inverted-U

Open Research Exeter

The antibiotic dosage of fastest resistance evolution: gene amplifications underpinning the inverted-U (dataset)

Catalán, Pablo

Explore Bristol Research

The Antibiotic Dosage of Fastest Resistance Evolution: gene amplifications underpinning the inverted-U

This is the final version. Available on open access from Oxford University Press via the DOI in this recordWhole-genome data are published and publicly available on ENA (https://www.ebi.ac.uk/ena) with accession number PRJEB28068. Other datasets can be downloaded from https://ore.exeter.ac.uk/repository/. All raw data are shown in supplementary figures, Supplementary Material online.The dataset associated with this article is located in ORE at: https://doi.org/10.24378/exe.3163To determine the dosage at which antibiotic resistance evolution is most rapid, we treated Escherichia coli
 in vitro, deploying the antibiotic erythromycin at dosages ranging from zero to high. Adaptation was fastest
 just below erythromycin’s minimal inhibitory concentration (MIC) and genotype-phenotype correlations
 determined from whole genome sequencing revealed the molecular basis: simultaneous selection for copy
 number variation in 3 resistance mechanisms which exhibited an ‘inverted-U’ pattern of dose-dependence,
 as did several insertion sequences and an integron. Many genes did not conform to this pattern, however,
 reflecting changes in selection as dose increased: putative media adaptation polymorphisms at zero antibiotic
 dosage gave way to drug target (ribosomal RNA operon) amplification at mid dosages whereas prophage-mediated drug efflux amplifications dominated at the highest dosages. All treatments exhibited E. coli
 increases in the copy number of efflux operons acrAB and emrE at rates that correlated with increases
 in population density. For strains where the inverted-U was no longer observed following the genetic
 manipulation of acrAB, it could be recovered by prolonging the antibiotic treatment at sub-MIC dosages.Engineering and Physical Sciences Research Council (EPSRC)Ramón Areces Postdoctoral FellowshipMinisterio de Ciencia, Innovación y Universidades/FEDE

The Antibiotic Dosage of Fastest Resistance Evolution: gene amplifications underpinning the inverted-U (article)

https://ore.exeter.ac.uk/repository/bitstream/10871/124652/3/msab025.pdf

The antibiotic dosage of fastest resistance evolution: gene amplifications underpinning the inverted-U (dataset)

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Universidad Carlos III de Madrid e-Archivo

Open Research Exeter

Explore Bristol Research

Open Research Exeter